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Gantenerumab Product Analysis
Ref Code: DMKC0149882 Publication Date: 02/09/2016 Author: Maha Elsayed gantenerumab Product Analysis DMKC0149882 | Published on 02/09/2016
Reference: DMKC0149882 First published: 02/09/2016
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TABLE OF CONTENTS
4 PRODUCT PROFILES 4 gantenerumab : Alzheimer's disease
LIST OF FIGURES
8 Figure 1: Gantenerumab for Alzheimer’s disease – SWOT analysis 9 Figure 2: Datamonitor Healthcare’s drug assessment summary of gantenerumab in Alzheimer’s disease 10 Figure 3: Datamonitor Healthcare’s drug assessment summary of gantenerumab in Alzheimer’s disease
LIST OF TABLES
4 Table 1: Gantenerumab drug profile 5 Table 2: Gantenerumab Phase III data in Alzheimer’s disease 6 Table 3: Gantenerumab Phase III trials in Alzheimer’s disease
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PRODUCT PROFILES
gantenerumab : Alzheimer's disease
PRODUCT PROFILE
Analyst Outlook Despite gantenerumab’s (Roche/MorphoSys) failure to demonstrate clinical efficacy in prodromal Alzheimer’s disease, a study examining efficacy in patients with mild Alzheimer’s disease (Marguerite RoAD) is ongoing. While Roche remains confident in gantenerumab’s disease-modifying potential, Datamonitor Healthcare’s expectations for the Marguerite RoAD trial are dim unless changes in the dosing regimen can be applied to influence clinical outcomes.
Drug Overview Gantenerumab is a fully humanized centrally and N-acting monoclonal antibody (MAb) that primarily targets fibrillar amyloid-beta (Alzforum, 2014). It acts by preventing amyloid-beta plaque formation, promoting microglia-mediated clearance (Bohrmann et al., 2012). This binding and clearance is essential as amyloid-beta accumulation is a hallmark feature of Alzheimer’s disease (Roche, 2014).
Gantenerumab is currently in Phase III development for the treatment of mild Alzheimer’s disease and for individuals prone to developing Alzheimer’s disease due to the presence of a genetic mutation (Biomedtracker, 2015; Medtrack, 2015). In December 2014, SCarlet RoAD, a Phase III study evaluating gantenerumab in prodromal patients, was discontinued (Biomedtracker, 2015).
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Table 1: Gantenerumab drug profile
Molecule gantenerumab
Phase of development Phase III
Mechanism of action Passive immunization against amyloid-beta
Originator MorphoSys
Marketing company Roche/MorphoSys
Targeted indication Mild Alzheimer’s disease
Formulation Subcutaneous injection
Pricing strategy Expected to be comparable to the average price of Enbrel, Humira, Remicade, and Stelara
Dosing frequency Every four weeks
Estimated approval date Q2 2019
Alternative names RG1450, RO4909832
Source: Biomedtracker; Medtrack
DEVELOPMENT OVERVIEW In December 2014, following a pre-specified futility analysis and upon the recommendation of the independent Data Monitoring Committee, Roche announced its decision to discontinue SCarlet RoAD, a Phase III trial examining the clinical effects of gantenerumab in prodromal Alzheimer’s disease. Marguerite RoAD, a Phase III trial initiated in March 2014, will nevertheless continue to investigate the efficacy and safety of gantenerumab in patients with mild Alzheimer’s disease (ClinicalTrials.gov identifier: NCT02051608). Gantenerumab is also involved in the ongoing DIAN TU (Dominantly Inherited Alzheimer Network Trials Unit) trial, which is investigating treatment options for individuals who are at risk of dominantly inherited Alzheimer's disease (Biomedtracker, 2015; ClinicalTrials.gov identifier: NCT01760005; Trialtrove, 2016).
The discontinued Phase III study is summarized in the table below.
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Table 2: Gantenerumab Phase III data in Alzheimer’s disease
Trial Sample size Target patients Study design Dosing tested Results Reference and duration
SCarlet RoAD 799 Patients with Randomized, Arm 1: Arm 1 or Arm 2 Biomedtracker; prodromal parallel-assignment, gantenerumab versus Arm 3: No Alzheimer’s
(NCT01224106) Alzheimer’s disease double-blind, 225mg SC difference in CDR- Association, 2015 placebo-controlled SB;
(Phase III) Arm 2: gantenerumab Mean % change 105mg SC from baseline in cortical composite
Arm 3: placebo SC SUVR at week 100:
Duration and Arm 1: -5.37% frequency: every four weeks for 104 Arm 2: +0.19% weeks Arm 3: -1.11%
CDR-SB = Clinical Dementia Rating Scale – Sum of Boxes; SC = subcutaneous; SUVR = standardized uptake value ratio
Source: various (see above)
Ongoing Phase III trials are summarized in the table below.
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Table 3: Gantenerumab Phase III trials in Alzheimer’s disease
Trial Sample size Target patients Study design Treatment arms Primary Start endpoints date/primary completion date
Marguerite RoAD 1,000 Patients with mild Randomized, Arm 1: 105/225mg Mean change from March 2014/July
Alzheimer’s disease parallel-assignment, gantenerumab SC baseline in ADAS- 2018 (NCT02051608) double-blind, every four weeks Cog13 scores at
placebo-controlled week 104 (Phase III) Arm 2: placebo SC
every four weeks Mean change from
baseline in ADCS-
Duration: 104 weeks ADL scores at week
104
Change from baseline in brain amyloid load over time at week 104
DIAN TU 210 Patients who are at Randomized, Arm 1: Change from December risk, with parallel-assignment, gantenerumab baseline in the DIAN 2012/September (NCT01760005) dominantly double-blind, 225mg SC every TU cognitive 2019 inherited placebo-controlled four weeks composite score at (Phase II/III) Alzheimer's disease week 52, 104, 156, Arm 2: placebo SC and 208
Arm 3: solanezumab 400mg IV every four weeks
Arm 4: placebo IV
Duration: 208 weeks
ADAS-Cog13 = Alzheimer's Disease Assessment Scale – Cognitive Subscale (13-item subscore); ADCS-ADL = Alzheimer's Disease Cooperative Study – Activities of Daily Living; DIAN TU = Dominantly Inherited Alzheimer Network Trials Unit; IV = intravenous; SC = subcutaneous
Source: Trialtrove; ClinicalTrials.gov
SCarlet RoAD study discontinued following negative pre-futility analyses
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In November 2010, Roche initiated SCarlet RoAD, a global pivotal Phase III study to measure the effects of gantenerumab in patients with prodromal Alzheimer’s disease (Mini-Mental State Examination scores of ≥24). SCarlet RoAD was the first Phase III study to test the therapeutic efficacy of a disease-modifying therapy in patients with prodromal Alzheimer’s disease. Roche decided to stop the study based on the results of its pre-planned futility analyses. While gantenerumab exerted a dose-dependent reduction of brain amyloid load, cerebrospinal fluid tau, and total tau – the first reported treatment effect on both hallmark biomarkers – this did not translate into a clinical response. The lack of effect, along with the recommendation by the independent Data Monitoring Committee, prompted Roche’s decision to discontinue the study (Biomedtracker, 2015; Alzheimer’s Association, 2015; CTAD abstract OC4, 2015; CTAD abstract OC5, 2015). With regards to safety, there were incidences of amyloid-related imaging abnormalities involving hemosiderosis and edema ranging between 6.6–19.2% (CTAD abstract OC4, 2015). Gantenerumab was well tolerated overall by patients with prodromal Alzheimer’s disease.
Roche presented an exploratory analysis of the SCarlet RoAD study at the 2015 Clinical Trials on Alzheimer’s Disease annual meeting, suggesting that patients with rapidly progressing Alzheimer’s disease may have had a treatment benefit with high-dose gantenerumab. Approximately one-third of patients were identified as fast progressors according to a model developed by Delor et al. (2013) based on the Alzheimer’s Disease Neuroimaging Initiative observational study. The cognitive function of fast-progressor subjects with high gantenerumab plasma concentrations declined less on the Alzheimer's Disease Assessment Scale – Cognitive Subscale (median change = 2.66) than those with low concentrations (median change = 4.83), medium concentrations (median change = 4.00), or placebo (median change = 6.00) at week 104. This suggests that there was an exposure-dependent effect, particularly among the more vulnerable subset of patients (CTAD abstract OC4, 2015).
Ongoing Marguerite RoAD and DIAN TU trials are assessing gantenerumab in different stages of the disease Despite the SCarlet RoAD failure, Roche is committed to another global pivotal Phase III study, Marguerite RoAD. This trial is examining the clinical effects of gantenerumab in mild Alzheimer’s disease patients at the same doses as those used in SCarlet RoAD. The study is expected to be fully completed in March 2019 (Biomedtracker, 2015).
Gantenerumab is also being explored alongside Eli Lilly’s amyloid-beta antibody solanezumab in the DIAN TU study. This trial, funded by the National Institute of Health and conducted by Washington University, will enroll cognitively normal patients with inherited mutations in a critical gene that almost guarantee that they will go on to develop early-onset Alzheimer’s disease later in life, as well as healthy controls (Washington University, 2012). The aim of the DIAN TU study is to gauge the preventative efficacy of the drug treatments over a two-year time period. Comparisons will not be made between the two MAbs.
SWOT ANALYSIS
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Figure 1: Gantenerumab for Alzheimer’s disease – SWOT analysis
Source: Datamonitor Healthcare
CLINICAL AND COMMERCIAL ATTRACTIVENESS The figures below depict Datamonitor Healthcare’s drug assessment summary of gantenerumab for Alzheimer’s disease in relation to the comparator product, Aricept (donepezil; Eisai/Pfizer).
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Figure 2: Datamonitor Healthcare’s drug assessment summary of gantenerumab in Alzheimer’s disease
Source: Datamonitor Healthcare
Figure 3: Datamonitor Healthcare’s drug assessment summary of gantenerumab in Alzheimer’s disease
Source: Datamonitor Healthcare
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Despite SCarlet RoAD setback, Roche retains gantenerumab as a disease-modifying drug In July 2015, Roche announced the failure of its SCarlet RoAD study to meet its primary clinical endpoints. This news did not impact the other ongoing Phase III studies, particularly gantenerumab’s Marguerite RoAD trial. Since the drug was found to be overall safe and well tolerated, Roche is continuing to examine gantenerumab’s therapeutic benefit in patients with a more advanced stage of the disease. Signs of potential efficacy in crenezumab, Roche’s other amyloid-beta antibody, in mild Alzheimer’s disease might have supported the decision to continue with Marguerite RoAD. However, despite the confidence Roche displays in gantenerumab, Datamonitor Healthcare’s outlook on the Marguerite RoAD study’s potential for success is dim, unless dose escalation can be carried out.
When comparing the various clinical trials conducted for the other amyloid-targeting MAbs that have either hinted at or indicated efficacy, the doses used in SCarlet RoAD were particularly low (the maximum dose for gantenerumab was 225mg versus 800mg for aducanumab for an average 80mg/kg subject). While the lower dose was motivated by safety reasons, it may have been insufficient to reach biological efficacy. In addition, it seems optimistic to expect to obtain a clinical efficacy response in mild patients when there was no response achieved in a prodromal pool of patients. With a mechanism targeting the earlier forms of Alzheimer’s disease pathology, it is unlikely that gantenerumab will be able to demonstrate clinical efficacy in a more advanced form of the disease unless the dose is scaled up.
“I think the major possibilities [for the failure of the SCarlet RoAD study] would include that the drug simply does not work or that it was dosed too low, and one wonders about dosing too low now in light of Biogen’s data [of aducanumab] [...] The other possibility is that they looked at the wrong subjects, but most of the emerging data are that mild or prodromal patients may be the most likely to show a benefit with these drugs, and they did indeed look at biomarker-positive prodromal patients. So, it does not seem as though they missed the boat on the patient population.”
US key opinion leader
Bibliography Alzforum (2014) End of the RoAD for Gantenerumab? Roche Declares Prodromal Alzheimer’s Trial Futile. Available from: http://www.alzforum.org/news/research-news/end-road-gantenerumab-roche- declares-prodromal-alzheimers-trial-futile [Accessed 29 September 2015].
Alzheimer’s Association (2015) Biomarker Results from Phase 3 Gantenerumab (Roche) Trial in Early Alzheimer’s. Available from: http://www.alz.org/aaic/_downloads/Wed-7am.pdf [Accessed 10 September 2015].
Bohrmann B, Baumann K, Benz J, Gerber F, Huber W, Knoflach F, Messer J, Oroszlan K, Rauchenberger R, Richter WF, Rothe C, Urban M, Bardroff M, Winter M, Nordstedt C, Loestscher H (2012) Gantenerumab: a novel human anti-A antibody demonstrates sustained cerebral amyloid- binding and elicits cell-mediated removal of human amyloid-. Journal of Alzheimer’s Disease, 280(1), 46–9
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CTAD abstract OC4 (2015) Efficacy and safety of gantenerumab from the Phase 3 Scarlet Road trial, a study of gantenerumab in patients with prodromal AD. Available from: http://www.ctad- alzheimer.com/sites/ctad.prod/files/files/ABSTRACTS%20CTAD2015.pdf [Accessed 6 November 2015].
CTAD abstract OC5 (2015) CSF and amyloid Pet biomarker data from the Phase 3 Scarlet Road trial, a study of gantenerumab in patients with prodromal AD. Available from: http://www.ctad- alzheimer.com/sites/ctad.prod/files/files/ABSTRACTS%20CTAD2015.pdf [Accessed 6 November 2015].
Delor I, Charoin J-E, Gieschke R, Retout S, Jacqmin P (2013) Modeling Alzheimer’s disease progression using onset time and disease trajectory concepts applied to CDR-SOB scores from ADNI. CPT Pharmacometrics Systems Pharmacology, 2(10)
Roche (2014) Roche provides update on gantenerumab development programme. Available from: http://www.roche.com/media/store/releases/med-cor-2014-12-19b.htm [Accessed 10 September 2015].
Roche (2015) Expected registration filing date. Available from: http://www.roche.com/research_and_development/who_we_are_how_we_work/pipeline.htm [Accessed 10 September 2015].
Washington University (2012) Investigational drugs chosen for major Alzheimer’s prevention trial. Available from: http://news.wustl.edu/news/Pages/24400.aspx [Accessed 24 September 2015].
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